This K23 application is designed to develop my career in patient-oriented research through a structured mentored program enabling a transition from my purely clinical role to one as a fully independent research investigator working in the pharmacogenomics of antithrombotic regimens. Platelets play a key role in the natural history of clinical atherothrombotic events and anti-platelet agents are highly effective in the prevention of coronary and stroke events. Aspirin (ASA) is still a mainstay of primary prevention in high risk persons. Failure of ASA to protect all individuals at risk has been attributed in part to suboptimal platelet suppression. The addition of another drug that inhibits platelets through a different pathway might benefit persons selected on the basis of a high risk phenotype. In European Americans, we have recently discovered a common A/G variant at rs12041331 locus in the intron1 of the PEAR1 gene that is associated with native and post-ASA platelet aggregation and increased PEAR1 protein levels in platelets. This finding has been replicated in an independent sample of African Americans and in the Framingham Heart Study. I have also completed a first-pass genome-wide association study (GWAS) for collagen-related platelet phenotypes pre and post-ASA, with a significant signal (p<10-11) on Chr 19, a region with genes possibly involved in platelet function. The studies I propose extend the science of these findings and will examine the role of PEAR1 variant on platelet responsiveness. My proposed studies include continued efforts to discover novel genes, using GWAS, in specific platelet activation pathways before and after low dose ASA. Discovery of novel genes may promote platelet pharmacogenomics research focusing on specific platelet pathways in at-risk primary prevention populations. Further in my proposed studies, I will create a new framework for translating findings into risk-stratification for primary prevention. Specifically, the proposed project aims to determine the extent to which a variant identified in the PEAR1 gene modifies the responsiveness of platelets to inhibition by clopidogrel alone and in combination with ASA in a high risk subset of GeneSTAR subjects (N=200) having both significant occult CAD identified by coronary CT angiography, and small vessel cerebrovascular disease identified by cranial MRI. This study has important public health implications given the notable potential impact of effective anti-platelet therapy on coronary disease and stroke outcomes in high risk persons. Identifying a high-risk population on the basis of phenotype and genotype may demonstrate persons in whom chemoprophylaxis can be tailored.